Disorders of cognition are generally characterized by symptoms of forgetfulness, confusion, memory loss, attentional deficits, and/or, in some cases, affective disturbances. These symptoms may arise as a result of the general aging process and/or from organic brain disease, cerebrovascular disease, head injury, or developmental or genetic defects.
The general decrease in cognitive function which accompanies the aging process is well accepted. The same phenomenon has been observed and documented in many lower mammals, including those routinely employed in pharmacological testing programs for screening and predicting usefulness for particular drugs in higher animals, including humans.
Although disorders of cognition often accompany the general aging process, presenile and senile primary degenerative dementia are the most common accepted causes of mental deterioration in the elderly. It has been estimated that at least 10 percent of persons over 60 years of age will eventually suffer severe mental deterioration. A much larger number will experience cognitive decline of sufficient severity to impede their activities.
Many of the symptoms of cognitive disorders, especially impaired memory, are associated with decreased acetylcholine synthesis and the impairment of cholinoreceptive neurons. In the hippocampus and cerebral cortex of patients suffering from primary degenerative dementia, for example, the level of the enzyme choline acetyltransferase (CAT) can be reduced by as much as 90% (see Davies, et al., The Lancet 1976;2:1403; Perry, et al., J. Neurol. Sci. 1977;34:247-265; and White, et al., The Lancet 1977;1:668-670).
Since CAT catalyzes the synthesis of acetylcholine from its precursors choline and acetyl coenzyme A, the loss of CAT reflects the loss of cholinergic, or acetylcholine-releasing, nerve endings in the hippocampus and cerebral cortex. There is abundant evidence that cholinergic terminals in the hippocampus are critically important for memory formation.
The cholinergic hypothesis suggests that drugs which restore acetylcholine levels or which mimic the action of acetylcholine (i.e., are cholinomimetic) are effective in correcting this deficit in neurotransmitter chemical and provide treatment of the memory impairment symptom of cerebral insufficiency. Considerable biochemical, pharmacological, and electrophysiological evidence supports the hypothesis that deficits in the cholinergic system underlie geriatric cognitive dysfunction (see Peterson C., Gibson G. E., Neurobiol. Aging 1983;4:25-30). Aged humans and nonhuman primates with decreased cognition show improved memory when they are treated, for example, with acetylcholinesterase inhibitors such as physostigmine. These agents increase the available supply of synaptic acetylcholine by inhibiting its hydrolysis.
Aminopyridines such as 3,4-diaminopyridine ameliorate age-related cognitive deficits by increasing the release of acetylcholine from presynaptic nerve terminals, thus increasing synaptic acetylcholine (see Davis HP, et al., Exp. Aging Res. 1983;9:211-214).
It has been known for some time that the natural alkaloid, muscarine, has the ability to act relatively selectively at autonomic effector cells to produce qualitatively the same effects as acetylcholine. Two alkaloids, pilocarpine and arecoline (the methyl ester of 1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxylic acid), have the same principal sites of action as muscarine and acetylcholine and are thus classified as having "muscarinic" action. Although these naturally occurring alkaloids are of great value as pharmacological tools, present clinical use is largely restricted to the use of pilocarpine as a miotic agent.
Recently it has been demonstrated that arecoline is effective in ameliorating some of the symptoms of cognitive disorders in patients clinically diagnosed as having presenile primary degenerative dementia. Significant improvement was observed in a test of picture recognition after administration of arecoline to patients in a double-blind study (see Christie, et al., Brit. J. Psychiatry 1981;138:46-50).
The use of cholinomimetic agents in multiple clinical trials has documented both the potential therapeutic utility of cholinergic agents and the high incidence of unwanted side effects (see Hollander E., et al., Brit. Med. Bull. 1986;42:97-100). Many of these unwanted side effects result from the nonselective stimulation of cholinergic receptors (of the muscarinic type) located throughout the body. Muscarinic receptors have been classified pharmacologically and at the molecular level into several subtypes (see Bonner T., Trends Pharmacol. Sci. 1989;(Suppl. on Subtypes of Muscarinic Receptors IV):11-15). The receptors responsible for the central cognition-enhancing effects of muscarinic cholinomimetic agents are generally defined as M.sub.1 (pharmacological definition) or m1 (molecular definition). Activation of peripheral M.sub.2 and M.sub.3 (or m2 and m3) receptors is thought to be responsible for the unwanted side effects of the currently available muscarinic agents (e.g., sweating, diarrhea, cramps, excessive salivation, etc). Thus, selective M.sub.1 (or m1) muscarinic agonists hold the best promise for selective improvement of cognitive function without the occurrence of unwanted side effects.
U.S. Pat. No. 5,306,718 covers final products prepared by the process of the instant invention.
A continuation-in-part application, U.S. Ser. No. 08/110,904 filed Aug. 24, 1993, is pending. Both of these are incorporated by reference.
Certain 3- or 4-ketoximes of 1-(lower alkyl)-1,2,5,6-tetrahydropyridines in which the oxygen is unsubstituted are disclosed in U.S. Pat. No. 3,004,979, having utility as parasympathomimetic agents acting on nonstriated muscle.
U.S. Pat. No. 4,710,508 describes O-substituted 1-(1,2,3,6-tetrahydro-1-methyl-3-pyridinyl)ketone oximes and O-substituted 1-(1,2,3,6-tetrahydro-4-pyridinyl)ketone oximes which are useful as analgesic agents or agents for the treatment of the symptoms of cerebral insufficiency characterized by decreased central acetylcholine production.
Dissertation Abstracts Int. B 1984;45(7):2120; CA102:113440m describes oxime-O-ethers of the following formula as having anticholinergic properties: ##STR1## wherein R is F, Cl, Br, NO.sub.2, OCH.sub.3, CF.sub.3, or CH.sub.3. Particularly relevant are pages 128-136, 166, 167, 198-203.
French Patent Number 2,086,292 describes 3-quinuclidinone oxime carbamates of the following formula having insecticidal and acaricidal activity. ##STR2## wherein R.sub.3 is alkyl, alkenyl, alkylidene, halogen, cyano, haloalkyl, haloalkenyl, alkoxy, etc; R.sub.1 and R.sub.2 are hydrogen, lower alkyl, acyl which may be substituted, lower alkenyl, or the group R--O--CH.sub.2 -- wherein R is methyl, ethyl, isopropyl; propyl-1,2-diene, allyl, 1-methyl-2-propenyl; phenyl or benzyl.
British Patent Application 2,258,652 covers azabicyclic oxime ether derivatives which are taught to be useful in stimulating muscarinic acetylcholine receptors. The compounds are represented by the formula ##STR3## wherein R is an alkyl of from 1 to 6.
U.S. Pat. No. 4,158,015 teaches a process for the stereoselective synthesis of the E-isomer of certain aryl alkyl ketoximes useful as insecticidals. The oximes are formed as a mixture of isomers and the mixture was isomerized with acid catalysis. The compounds are of the type ##STR4## wherein R is alkyl, cycloalkyl, alkenyl, any of which can be substituted by halogen, hydroxy, alkoxy, alkylsulfonyl, cyano, nitro, carboalkoxy, or acyl. The process discussed does not work in the present invention to prepare the desired pure Z-oxime.